GENETIC MODULATION OF THE TUMOR MICROENVIRONMENT IN THE APCMIN/+ MOUSE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 抗癌治疗通常针对的是肿瘤细胞。胸苷酸合成酶(TS)的抑制剂多年来一直被用于各种癌症的临床治疗。尽管对控制肿瘤对TS抑制剂反应的遗传和分子因素进行了广泛的研究，但其临床疗效仍然有限。在这个项目中，我们提出了一种新的方法来提高肿瘤对这些药物的反应。肿瘤中有大量异质性的非肿瘤细胞。这些细胞包括宿主来源的细胞，如成纤维细胞、巨噬细胞、淋巴细胞、内皮细胞等。它们与细胞外基质一起构成肿瘤间质或微环境。通过分泌一系列细胞因子、生长因子、激素等，它们在肿瘤的生长和发展以及对治疗的反应中发挥关键作用。我们将验证肿瘤对TS抑制剂的反应是由浸润性基质细胞的化疗敏感性决定的假设。我们利用了在小肠和结肠腺瘤性息肉自发发展的ApcMin/+小鼠。通过骨髓移植，我们产生了嵌合小鼠，其中基质细胞的化疗敏感性与肿瘤不同，并预测这些小鼠的肿瘤将表现出反映基质细胞化疗敏感性的药物反应。其具体目的是：1)确定TS抑制剂对间质间质细胞的影响，并确定TS抑制剂反应的介质；2)检测TS下调间质细胞对肿瘤对TS抑制剂的反应的影响；3)针对肿瘤相关的间质细胞直接增敏TS抑制剂。正在测试的假设将为开发使用基质细胞的新治疗策略铺平道路，以改进针对肿瘤细胞的治疗，以确保药物诱导的癌细胞死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Anti-cancer therapy has typically been targeted on neoplastic cells. Inhibitors of the enzyme thymidylate synthase (TS) have been used for many years in the clinical management of a variety of cancers. In spite of the extensive research on the genetic and molecular factors governing tumor response to TS inhibitors, its clinical efficacy remains limited. In this project, we propose a novel approach to increase tumor response to these agents. Tumors are infiltrated with a heterogeneous population of non-neoplastic cells. These include host-derived cells such as fibroblasts, macrophages, lymphocytes, endothelial cells, etc. Together with extracellular matrix, they make up the tumor stroma or microenvironment. By secreting an array of cytokines, growth factors, hormones, etc., they play a critical role in tumor growth and progression, and response to therapy. We will test the hypothesis that tumor response to TS inhibitors is governed by the chemosensitivity of infiltrating stromal cells. We utilized the ApcMin/+ mice which spontaneously develop adenomatous polyps in the small intestine and the colon. By bone marrow transplantation we generated chimeric mice wherein the chemosensitivity of stromal cells is distinct from that of the tumor and predicted that tumors in these mice will show a drug response that reflects the chemosensitivity of stromal cells. The specific aims are: 1) to determine the impact of TS inhibitors on cells in the stromal compartment and identify mediators of response to TS inhibitors; 2) to examine the effect of TS down regulation in stromal cells on tumor response to TS inhibitors; and 3) to direct sensitization to TS inhibitors specifically to tumor associated stromal cells. The hypothesis being tested will pave the way for development of new treatment strategies using stromal cells to improve therapies targeted at tumor cells to ensure drug induced cancer cell death.